title: The non-protein amino acid BMAA is misincorporated into human proteins in place of L-serine causing protein misfolding and aggregation.
abstract: Mechanisms of protein misfolding are of increasing interest in the aetiology of neurodegenerative diseases characterized by protein aggregation and tangles including Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), Lewy Body Dementia (LBD), and Progressive Supranuclear Palsy (PSP). Some forms of neurodegenerative illness are associated with mutations in genes which control assembly of disease related proteins. For example, the mouse sticky mutation sti, which results in undetected mischarging of tRNA(Ala) with serine resulting in the substitution of serine for alanine in proteins causes cerebellar Purkinje cell loss and ataxia in laboratory animals. Replacement of serine 422 with glutamic acid in tau increases the propensity of tau aggregation associated with neurodegeneration. However, the possibility that environmental factors can trigger abnormal folding in proteins remains relatively unexplored. We here report that a non-protein amino acid, β-N-methylamino-L-alanine (BMAA), can be misincorporated in place of L-serine into human proteins. We also report that this misincorporation can be inhibited by L-serine. Misincorporation of BMAA into human neuroproteins may shed light on putative associations between human exposure to BMAA produced by cyanobacteria and an increased incidence of ALS.
authors.affiliation: Cell Biology Group, School of Medical and Molecular Biosciences, University of Technology Sydney, Ultimo, New South Wales, Australia.
authors.forename: Rachael Anne
authors.initials: RA
authors.lastname: Dunlop
authors.forename: Paul Alan
authors.initials: PA
authors.lastname: Cox
authors.forename: Sandra Anne
authors.initials: SA
authors.lastname: Banack
authors.forename: Kenneth John
authors.initials: KJ
authors.lastname: Rodgers
mesh_terms: D000599:Amino Acids, Diamino / Q000032:analysis* / Q000378:metabolism; D018929:Cell Culture Techniques; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D000458:Cyanobacteria / Q000737:chemistry*; D000087522:Cyanobacteria Toxins; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000737:chemistry*; D057165:Proteostasis Deficiencies / Q000235:genetics*; D053719:Tandem Mass Spectrometry; D014316:Tritium
chemical_list: D000599:Amino Acids, Diamino; D000087522:Cyanobacteria Toxins; D009419:Nerve Tissue Proteins; D014316:Tritium; C001824:beta-N-methylamino-L-alanine; D007770:L-Lactate Dehydrogenase